Systemic lupus erythematosus (SLE) is a complex autoimmune disease with a broad spectrum of clinical manifestations that affect several organs. SLE affects millions of individuals, with women and minorities disproportionately burdened, and is associated with significant morbidity and mortality. Despite considerable progress made towards understanding the disease and the identification of the central roles plasma cells (PCs) and autoreactive antibody secreting cells (ASCs) play in SLE pathogenesis, most therapeutic approaches remain broadly immunosuppressive, anti-inflammatory, or palliative, which highlights the urgent need for novel therapies. Due to the essential role of auto-antibodies in the amplification of auto-immunity, a goal in lupus therapy is the elimination of auto-reactive ASCs. Karyopharm Therapeutics pioneered the development of Selective Inhibitors of Nuclear Export (SINE), and is investigating their utility in auto-immune diseases in collaboration with the Anolik laboratory at the University of Rochester Medical Center. Together we have shown that inhibiting nuclear export with KPT-350, a SINE, strongly and selectively ablates auto-reactive PCs by targeting pathways that are critical for their generation, survival, and recruitment into inflamed kidneys. Specifically, we have shown that KPT-350 selectively inhibits the production of auto-reactive ASCs and has a compelling effect on B-cell germinal center formation/stability, prevents expansion of memory T follicular helper cells, and markedly reduces mRNA expression of molecules critical for survival and recruitment of auto-reactive ASCs. In the proposed project, we will further define the efficacy of SINE treatment and identify viable combination and maintenance therapies to accelerate the translation of these novel compounds into SLE clinical trials. In Aim 1, we will define the optimal dosage conditions to restrain murine lupus progression after withdrawal of SINE therapy by (i) determining the duration of the SINE effect and defining the need for maintenance therapy, and (ii) defining the duration of the SINE effect on NF?B inhibition. In Aim 2, we will examine the effects of combination modality therapy on murine autoreactive PCs by (i) evaluating the efficacy and duration of SINE and proteasome inhibitors on autoimmune disease relapse, (ii) determining the effects of single vs combination therapy on PCs in SLE, and (iii) defining the impact of factors involved in the maintenance of autoreactive PCs. Finally, Aim 3 will expand our studies to human SLE by (i) defining the role of NF?B survival signals in SLE patient PCs, (ii) examining the effect SINE treatment has on SLE PC survival, (iii) defining the signals required for SLE bone marrow (BM) PC survival, (iv) identifying the source of PC survival factors in the BM, and (v) demonstrating that SINE therapy inhibits B-cell differentiation. Our goal is to delineate an efficacious combination dosing strategy, using a novel approach that targets key synergistic pathways in SLE disease pathogenesis, with the long term goal of delivering an improved therapy for SLE. Successful completion of these studies will allow us to pursue commercialization objectives and move SINE compounds into extensive preclinical safety testing.